Capsules for oral preparations and capsule preparations for oral administration

ABSTRACT

This invention offers capsules for oral preparation which is useful for colon diseases such as colon cancer, ulcerative colitis, constipation and diarrhea and for systemic diseases such as osteoporosis and which does not undergo any change at all in stomach and in small intestine but firstly start to disintegrate upon arriving at large intestine and, at the same time, quickly release the drug therefrom wherein the capsule base therefor is hydroxypropylmethylcellulose (HPMC) or polyethyleneglycol-compounded HPMC, gelatin or agar and, on the surface of said capsule base in which powder or liquid containing a pharmacologically active substance is encapsulated, a double-coated structure comprising an inner layer consisting of a cationic copolymer and an outer layer consisting of anionic copolymer is formed.

FIELD OF THE INVENTION

1. Background of the Invention

This invention relates to capsules for preparations for oraladministration and also to capsule preparations for oral administrationusing said capsules. More particularly, this invention relates tocapsules being able to be administered orally in which pharmacologicallyactive substance depending upon the object can be encapsulated and whichis firstly disintegrated upon arriving at the large intestine wherebythe pharmacologically active substance can be efficiently releasedtherefrom and also relates to capsule preparations using said capsuleswhere said preparations are pharmaceutical preparations useful for colondiseases such as colon cancer, ulcerative colitis, constipation anddiarrhea and for systemic diseases such as osteoporosis.

2. Description of Related Art

In recent years, great effort has been made for developing theintestinal delivery art where the preparation after oral administrationis not disintegrated in stomach and small intestine but is disintegratedjust upon arriving at the large intestine. The reason is that such amethod in place of conventional intravenous administration, transnasaladministration, rectal administration, etc. greatly reduces the burdenof the patients as compared with those conventional methods.

Examples of the known intestinal delivery art which have been known upto now are an oral preparation where a polymer which is soluble only atpH 5.5 or higher and an insoluble polymer are combined whereby largeintestine is a target for releasing the drug (European Patent 49,590); asolid oral dosage form coated with an appropriate amount of anionicpolymer (trade name: Eudragit S; manufactured by Rohm) which is solubleat pH 7.0 or higher (International Laid-Open Patent WO 83/00435); anoral preparation coated with a composition in an appropriate ratio ofanionic copolymer which is soluble at pH 7.0 or higher (trade name:Eudragit S or L; manufactured by Rohm) and a methacrylate copolymerwhich is hardly soluble in water (trade name: Eudragit RS; manufacturedby Rohm) (European Patent 225,189); an osmotic pressure pump preparationwhich is coated with an enteric coating polymer (Belgian Patent903,502); and an oral pharmaceutical preparation delivering to largeintestine where an internal layer which is soluble at pH 7.0 or higheris coated with a gelled polymer layer as an intermediate layer and thenfurther coated with a stomach-resisting external layer which is solubleat pH 5.5 or higher (Japanese Laid-Open Patent Hei-04/501,411).

However, each of those known art relates to a preparation showing thetime-depending release of drugs and their specificity to large intestineis high, cannot be said to be high. Thus, there are problems that, forexample, when the staying time in small intestine is long, thepreparation is disintegrated in the small intestine while, when thestaying time in small and large intestines is short, the preparation isnot disintegrated but is excreted outside as it is.

In order to improve such problems, the inventors of this inventionproposed an oral pharmaceutical preparation of a type of releasing fromlower gastrointestinal tracts having a high specificity to largeintestine (International Laid-Open Patent WO 94/10983). This product ischaracterized in that it is a solid preparation having a double-coatedstructure where molded tablets or granules with pressure are used ascores and they are coated with an inner layer consisting of a cationiccopolymer and an outer layer consisting of an anionic copolymer. Thispreparation has a very good specificity to large intestine and makes itpossible to release the drug to the large intestine as a target in amore reliable manner. However, in spite of such an improvement,satisfactory releasing and absorbing efficiencies are not alwaysachieved in the case of hardly-soluble substances and polymers.Therefore, it has been a very important matter to conduct a drug designdepending upon the physical and chemical properties of the drug so thatabsorbing efficiency of the drug is further improved.

SUMMARY OF THE INVENTION

As a solution for the above-mentioned problems, this invention offerscapsules for oral preparations, characterized in that, surface of thecapsule base consisting of hydroxypropylmethylcellulose, a mixture ofpolyethylene glycol with hydroxypropylmethylcellulose, gelatin or agaris successively coated with a cationic copolymer and an anioniccopolymer and also offers capsule preparations for oral administrationwhere a pharmacologically active substance is encapsulated in saidcapsules.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a drawing which shows that a capsule preparation which iscoated with a cationic copolymer only is disintegrated in stomach.

FIG. 2 is a drawing which shows that a double-coated capsule preparationis disintegrated in large intestine.

FIG. 3 is a drawing which shows the disintegrating state of a capsule #5where each of the coating amounts of the inner and the outer layers ismade 10 mg.

FIG. 4 is a drawing which shows the disintegrating state of a capsule #5where each of the coating amounts of the inner and the outer layers ismade 15 mg.

FIG. 5 is a drawing which shows the disintegrating state of a capsule #5where each of the coating amounts of the inner and the outer layers ismade 20 mg.

FIG. 6 is a drawing which shows the disintegrating state of a capsule #5where each of the coating amounts of the inner and the outer layers ismade 25 mg.

FIG. 7 is a drawing which shows the disintegrating state of a capsule #5where each of the coating amounts of the inner and the outer layers ismade 30 mg.

FIG. 8 is a drawing which shows dissolution of prednisolone from acapsule preparation of prednisolone (a liquid preparation) is quick ascompared with the case of tablets.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

This invention relates to the capsules as mentioned above and also tocapsule preparations using the same where the capsule in which apharmacologically active substance either in a form of liquid or powderis encapsulated is characterized in that said capsule has a specificbase composition and also has a double-coated structure where thesurface of the base has a cationic copolymer as an inner layer and ananionic copolymer as an outer layer. Here, the base for the capsule ishydroxypropylmethylcellulose, a mixture of polyethylene glycol withhydroxypropylmethylcellulose, gelatin or agar. Representative examplesof the cationic copolymer which constitutes the inner layer of thedouble-coated layers are copolymer of methyl methacrylate with butylmethacrylate and dimethylaminoethyl methacrylate and polyvinylacetaldiethylaminoacetate (AEA) (such as Eudragit E; manufactured by Roehm).Examples of viscosity of those cationic copolymer are around 1-30centistokes (10 g; 100 ml methanol). Examples of the anionic copolymerwhich constitutes the outer layer are a copolymer of methacrylic acidwith methyl methacrylate (such as Eudragit S; manufactured by Roehm),hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcelluloseacetate succinate, carboxymethylethylcellulose and cellulose acetatephthalate. Examples of viscosity of those anionic copolymers are around5-60 centistokes (10 g; 100 ml methanol).

There is no particular limitation for the pharmacologically activesubstance to be encapsulated in the capsules so far as it is a substancewhich is effective when released in the lower gastrointestinal tractsand any of such substances may be used.

Thus, its examples are polypeptides, anti-inflammatory agents,anti-tumor agents, antibiotics, chemotherapeutic agents, remedies forulcerative colitis, remedies for irritable colon syndrome, steroidalpreparations, vitamins, drugs for diarrhea (including those forconstipation), anti-sense drugs and immunosuppressants. To be morespecific, the examples are insulin, angiotensin, vasopressin,calcitonin, gastrin, somatostatin, desmopressin, LH-RH (luteinizinghormone-releasing hormone), glucagon, oxytocin, gastrin, somatomedin,secretin, EGF(epidermal growth factor), α-hANP (α-human atrialnatriuretic peptide), enkephalin, endorphin, GM-CSF(granulocyte-macrophage colony stimulating factor), G-CSF (granulocytecolony stimulating factor), human growth hormone, t-PA (Tissueplasminogen activator), TNF (tumor necrosis factor), TCGF (T-cell growthfactor), ACTH (adrenocorticogropic hormone), interleukins, interferon,EPO (erythropoietin), urokinase, neocarcinostatin, immunoglobulin,muramyl dipeptide, MSH (melanocyte stimulating hormone), neurotensin,bombesin, endothelin, VIP (vasoactive intestinal polypeptide), CCK-8(cholecystokinin 8), PTH (parathyroid hormone), CGRP (calcitoningene-related peptide), TRH (thyrotropin-releasing hormone), diclofenacsodium, loxoprofen sodium, tenoxicam, lornoxicam, meloxicam, piroxicam,celecoxib, nimesulide, indomethacin, bleomycin, fluorouracil, tegafur,tegafur uracil, cisplatin, doxorubicin, cefpiramide sodium, cefsulodinsodium, kanamycin, erythromycin, cefoperazone sodium, ceftizoximesodium, ceftriaxone sodium, cefmetazole sodium, cefotaxime sodium,cefazolin sodium, gentamycin, ceftezole sodium, cefamandole sodium,streptomycin, penicillin, tetracycline, salazosulfapyridine, budesonide,betamethasone sodium phosphate, prednisolone, mesalazine,methylprednisolone, hydrocortisone, beclometasone, β-carotene, sodiumascorbate, tocopherol, bisacodyl, picosulfate sodium, senna extract andcyclosporin. Incidentally, it goes without saying that thosepharamcologically active substances cover their usualmedically-acceptable inorganic and organic basic salts as well.

Incidentally, with regard to an anti-inflammatory agent, acyclooxygenase (COX)-2 inhibitor is preferred. In addition, thepharmacologically active substance to be encapsulated in the capsule aswell as the composition consisting of that and the following variousadditives to be added thereto are to be usually in a neutral oralkaoline region of around pH 7 or, preferably, lower than that. Ifnecessary, additives such as vehicle, liquid agent, absorbefacient andothers for various purposes may be compounded in the capsule. Thevehicle at that time is appropriately selected from lactose, starch,talc, lactose, calcium hydrogen phosphate, sodium hydrogen phosphate,synthetic aluminum silicate, megnesium metasilicate aluminate, aluminummagensium hydroxide, synthetic hydrotalcite, magensium silicate, naturalaluminum silicate, potassium, carbonate, calcium carbonate, sodiumcarbonate, magnesium oxide, magnesium carbonate, sodium hydrogencarbonate, potassium hydrogen carbonate, silicic acid anhydride, lightsilicic acid anhydride, sodium hydroxide, tetrasodium pyrophosphate,anhydrous sodium pyrophosphate, anhydrous trisodium phosphate,dipotassium phosphate, anhydrous sodium sulfite, sodium ditartrate, etc.Incidentally, in adjusting the pH of the pharmaceutical-containingcomposition in the capsules, the adjustment may be conducted byselecting from those vehicles if necessary.

In the case of a liquid preparation, the use of glycerol, soybean oil,polyethylene glycol 400 (PEG 400), docosahexaenoic acid,eicosapentaenoic acid, pirotiodecane (chemical name:1-[2-(decylthio)ethyl]azacyclopentan-2-one), sesame oil, safflower oil,cotton seed oil and olive oil may be exemplified. Further, with anobject of accelerating the absorption of the pharmacologically activesubstance, absorbefacient such as sucrose fatty acid ester,glycyrrhizinate, glycyrrhetinic acid, bile acid and conjugated compoundthereof, pirotiodecane, glycerol fatty acid ester, adipic acid, basicamino acid, polyethylene glycol, sodium caprate, sodium dodecyl sulfateand sodium deoxycholate may be added.

An example of the method for the manufacture of the preparation is asfollows. Liquid in which a pharmacologically active substance or powdercontaining it and various additives are dissolved or dispersed is filledin the above-mentioned base capsule. Then a cationic copolymer is coatedon the surface of the capsule after filling and then an anioniccopolymer is coated thereon. In conducting the coating, the core is, forexample, previously heated at 30-50° C. and then a coating solution iscontinuously sprayed thereon at 30-50° C.

An increase in weight by coating the cationic copolymer and the anioniccopolymer or, in other words, the coated amount is important as apractical and essential condition for the capsules for oraladministration of the present invention. Said coating amount may varydepending upon the size of the capsule. Thus, the amount for inner layer(a cationic copolymer) and that for outer layer (an anionic copolymer)vary depending upon the size of the capsule and each of them is 5-200mg, preferably 10-100 mg or, more preferably, 15-60 mg. To be morespecific, the preferred amount is 35-60 mg, 30-50 mg, 25-35 mg, 20-30 mgor 15-25 mg each for the capsules of the sizes #1, #2, #3, #4 or #5,respectively. Optimum coating amount is around 45 mg, around 40 mg,around 30 mg or around 20 mg for the capsule of #1, #2, #3 or #5,respectively. Incidentally, the total coating amount of inner and outerlayers is two-fold weight of the above-mentioned amount.

With regard to the coating amount for each of inner and outer layers,their ratio by weight may be from around 1:2 to around 2:1 but, usually,it is preferred to make it about in the same amount each.

Since there are capsules of various sizes, the above-mentioned weightrange is regulated as 0.08-0.13 mg/mm² (the optimum amount being around0.10 mg/mm²) in terms of the coating amount to the surface area of thecapsule. This corresponds to any of the sizes of from #1 to #5 of thecapsule.

When the coating amount in each of inner and outer layers is outside of5-200 mg or is outside of the above-exemplified ranges, it is difficultto achieve the capsules which are disintegrated in large intestine andalso to achieve the capsule preparations using said capsules.

As a result of this preparation, disintegration is firstly initiatedupon arriving at the large intestine and, at the same time, thepharmacologically active substance is quickly released. When a liquidpreparation is filled in the inner part of the capsule, thepharamcologically active substance is efficiently dispersed even in thelarge intestine where water content is little. Accordingly, localconcentration in the tissues of the large intestine smoothly increaseswhereby an excellent absorbing efficiency into blood is achieved.

The present invention will now be further illustrated by way of thefollowing examples. It goes without saying, however, that this inventionis not limited by those examples.

EXAMPLES Example 1

<Manufacture of Capsules>

Hydroxypropylmethylcellulose (HPMC) capsules #3 (weight: about 50 mg;the same being used hereinafter as well) was coated with a solutionhaving the following composition.

Eudragit E 7.0 parts by weight Ethanol 70.0 parts by weight Water 19.5parts by weight Talc 3.5 parts by weight

The actual operation was that the above solution of 50° C. was coated bymeans of a continuous spraying onto the core of the capsule base whichwas previously heated at 50° C. An increase in weight of the core was 30mg. After spraying, the core was dried and a solution having thefollowing composition of 50° C. was further coated by means of acontinuous spraying onto the previously coated core which was previouslyheated at 50° C.

Eudragit S 7.0 parts by weight Ethanol 70.0 parts by weight Water 18.8parts by weight Talc 3.5 parts by weight Polyethylene glycol 6000 0.7part by weight

An increase in weight was 30 mg.

Example 2

<Manufacture of Double-Coated Barium Sulfate Capsules>

Powder containing barium sulfate in the following formulation was filledin an HPMC capsule #3 to prepare a capsule having a weight of 425 mg.

Barium sulfate 375 mg

This capsule core was coated with a solution having the followingcomposition.

Eudragit E 7.0 parts by weight Ethanol 70.0 parts by weight Water 19.5parts by weight Talc 3.5 parts by weight

Thus, a coating was conducted by a continuous spraying of the abovesolution of 50° C. onto the core which was previously heated at 50° C.An increase in the weight of the core as a result of the inner layercoating was 30 mg. After spraying, the coated core was dried, heated at50° C. and coated with a continuous spraying of a solution having thefollowing composition kept at 50° C.

Eudragits 7.0 parts by weight Ethanol 70.0 parts by weight Water 18.8parts by weight Talc 3.5 parts by weight Polyethylene glycol 6000 0.7part by weight

An increase in weight as a result of the outer layer coating was 30 mg.

<Manufacture of Barium Sulfate Capsules Coated with Cationic Copolymer>

Meanwhile, for comparison, powder containing barium sulfate in thefollowing formulation was filled in an HPMC #3 capsule to manufacture acapsule having a weight of 425 mg.

Barium sulfate 375 mg

Incidentally, this core was coated with a solution having the followingcomposition.

Eudragit E 7.0 parts by weight Ethanol 70.0 parts by weight Water 19.5parts by weight Talc 3.5 parts by weight

The actual operation was that the above solution of 50° C. was coated bymeans of a continuous spraying onto the core which was previously heatedat 50° C. An increase in weight of the core was 30 mg.

Test Example 1

<An in vivo Test of Barium Sulfate Capsules in Dogs>

Barium sulfate capsules manufactured in Example 2 were administered todogs and X-ray pictures were taken periodically whereby the transfer anddisintegration in gastrointestinal tracts were observed. The result wasthat, as shown in FIG. 1, barium sulfate capsules coated with a cationiccopolymer (comparative example) were disintegrated in stomach while, asshown in FIG. 2, double-coated barium sulfate capsules (example of thisinvention) were disintegrated in large intestine.

Test Example 2

<Evaluation of Optimum Coating Amount by an in vivo Test in Dogs UsingBarium Sulfate capsules>

Taking the Test Example 1 into consideration as well, an optimum coatingamount to capsules was evaluated. A double coating by the sameformulations as in Example 2 was conducted in different coating amounts(i.e., in different increase in weight) on capsules having differentsizes (from 190 1 to 190 5). Incidentally, in all cases, coating amountsof inner layer (a cationic copolymer) and outer layer (an anioniccopolymer) were made same.

Specific mode of the test and the result thereof are as follow.

Thus, at first, five kinds of barium capsules were prepared usingcapsules of #5. The coating amount for each of inner and outer layerswas 10 mg for the lowest while it was 30 mg for the highest. Fourbeagles were used and each five capsules were orally administered toeach animal and the behavior of the capsules after administration wasobserved by taking X-ray pictures.

A shown in Table 1, when capsules #5 were used, disintegration of thepreparations in the case where coating amount in each of inner and outerlayers was 15-25 mg was 100% in large intestine while, in the case ofother coating amounts, there were a few preparations wheredisintegration was noted in small intestine (capsule number 5-1) ornon-disintegrated preparation was excreted into feces (capsule number5—5).

Incidentally, the term “fig. no” in Table 1 stands for FIG. 3 to FIG. 7attached.

Similarly, capsules of #3 were used and preparations where coatingamount in each of inner and outer layers was 20-40 mg were prepared.Then disintegration of the preparations by an in vivo test using thedogs was investigated whereupon, as shown in Table 2, a large intestinespecificity of 100% was noted in the preparations when a coating amountwas 25-35 mg. Further, in vivo disintegration tests were conducted usingthe dogs for capsules #2 (Table 3) or capsules # 1 (Table 4) whereupon100% disintegration which was specific to large intestine was confirmedin the case where the coating amounts were 30-50 mg and 35-60 mg foreach of inner and outer layers for the capsules #2 and capsules #1,respectively.

TABLE 1 Investigation on Optimum Coating Amount for # 5 CapsulePreparations Coating Amount Numbers (mg) for of Caps Inner OuterExcreted Layer Layer Numbers of Caps into Feces Cap- (Cationic)(Anionic) Disintegrated in without sule Fig of of Small Large Disin- No.No. Capsules Capsules Intestine Intestine tegration 5-1 3 10 10  8 (40%)12 (60%)  0 (0%) 5-2 4 15 15 0 (0%) 20 (100%) 0 (0%) 5-3 5 20 20 0 (0%)20 (100%) 0 (0%) 5-4 6 25 25 0 (0%) 20 (100%) 0 (0%) 5-5 7 30 30 0 (0%)10 (50%)  10 (50%)

TABLE 2 Investigation on Optimum Coating Amount for # 3 CapsulePreparations Coating Amount (mg) for Numbers of Inner Outer Caps LayerLayer Numbers of Caps Excreted (Cationic) (Anionic) Disintegrated ininto Feces Capsule of of Small Large without No. Capsules CapsulesIntestine Intestine Disintegration 3-1 20 20  5 (25%) 15 (75%)  0 (0%)3-2 25 25 0 (0%) 20 (100%) 0 (0%) 3-3 30 30 0 (0%) 20 (100%) 0 (0%) 3-435 35 0 (0%) 20 (100%) 0 (0%) 3-5 40 40 0 (0%) 15 (75%)   5 (25%)

TABLE 3 Investigation on Optimum Coating Amount for # 2 CapsulePreparations Coating Amount (mg) for Numbers of Inner Outer Caps LayerLayer Numbers of Caps Excreted (Cationic) (Anionic) Disintegrated ininto Feces Capsule of of Small Large without No. Capsules CapsulesIntestine Intestine Disintegration 2-1 25 25  5 (25%) 15 (75%)  0 (0%)2-2 30 30 0 (0%) 20 (100%) 0 (0%) 2-3 40 40 0 (0%) 20 (100%) 0 (0%) 2-450 50 0 (0%) 20 (100%) 0 (0%) 2-5 60 60 0 (0%) 10 (50%)  10 (50%)

TABLE 4 Investigation on Optimum Coating Amount for # 1 CapsulePreparations Coating Amount (mg) for Numbers of Inner Outer Caps LayerLayer Numbers of Caps Excreted (Cationic) (Anionic) Disintegrated ininto Feces Capsule of of Small Large without No. Capsules CapsulesIntestine Intestine Disintegration 1-1 30 30  4 (20%) 16 (80%)  0 (0%)1-2 35 35 0 (0%) 20 (100%) 0 (0%) 1-3 46 45 0 (0%) 20 (100%) 0 (0%) 1-460 60 0 (0%) 20 (100%) 0 (0%) 1-5 70 70 0 (0%) 10 (75%)   5 (25%)

It is believed from the above results that, since disintegration insmall intestine was noted when the coating amount for each of inner andouter layers was 10 mg in the case of capsule #5, it is not possible toarrive specifically to large intestine when the coating amount is lessthan that. In addition, since excretion of non-disintegratedpreparations into feces was noted when the coating amount was 30 mg,there will be a possibility that, in the capsule #5, disintegration willnot take place when the coating amount is more than that.

For the capsules in other sizes, it was evaluated from the result of thein vivo disintegration test that, when the coating amount for thecapsule of each size is more than the range as shown in the followingTable 5, an object of the preparation would not be achieved.

TABLE 5 Optimum Minimum Maximum Outer Coating Coating Coating CapsuleDiameter Length Amount Amount Amount Size (#) (mm) (mm) (mg) (mg) (mg) 16.9 20.9 45 35 60 2 6.35 19.3 40 30 50 3 5.82 17.3 30 25 35 5 4.89 12.420 15 25

Example 3

<Manufacture of Prednisolone Capsules (Liquid) and Tablets>

A liquid preparation containing prednisolone was manufactured accordingto the following formulation and filled in HPMC capsules #3 to preparecapsule preparations each weighing 150 mg.

Prednisolone  3.0 parts by weight Sodium deoxycholate 10.0 parts byweight PEG 400 87.0 parts by weight

For comparison, powder containing prednisolone was manufacturedaccording to the following formulation and made into tablets of 7 mmdiameter and 200 mg weight using a tablet-manufacturing machine.

Prednisolone 10.0 parts by weight Lactose 69.0 parts by weightCrystalline cellulose 10.0 parts by weight Polyvinylpyrrolide (PVP) 10.0parts by weight Magnesium stearate  1.0 parts by weight

Each of the cores was coated with a solution having the followingcomposition.

Eudragit E 7.0 parts by weight Ethanol 70.0 parts by weight Water 19.5parts by weight Talc 3.5 parts by weight

An inner layer was prepared by a continuous spraying of theabove-mentioned solution of 50° C. onto a core which was previouslyheated at 50° C. An increase in the core was 30 mg for a capsule and was16 mg for a tablet. After spraying, the coated core was dried and wasfurther sprayed with a solution having the following composition.

Eudragit S 7.0 parts by weight Ethanol 70.0 parts by weight Water 18.8parts by weight Talc 3.5 parts by weight Polyethylene glycol 6000 0.7part by weight

Thus, the above-mentioned solution of 50° C. was continuously sprayedonto a core which was previously heated at 50° C. An increase in thecore as a result of coating the outer layer was 30 mg for a capsule andwas 16 mg for a tablet.

Test Example 3

An in vivo Elution Test of Prednisolone Capsules (Liquid) and Tablets

Test of elution of prednisolone was conducted for prednisolone capsulesand tablets manufactured in Example 3 by a flow-through-cell method(FTC). The result was that, as shown in FIG. 8, quick elution of themain ingredient was noted in capsules as compared with tablets.

Example 4

Manufacture of Calcitonin Capsules (Powder)

Powder containing calcitonin was manufactured according to the followingformulation and filled in HPMC capsules #3 to manufacture capsules eachweighing 150 mg.

Calcitonin 10.0 parts by weight Sodium caprate 45.0 parts by weightDipotassium glycyrrhizinate 45.0 parts by weight

The capsules were coated with a solution having the followingcomposition.

Eudragit E 7.0 parts by weight Ethanol 70.0 parts by weight Water 19.5parts by weight Talc 3.5 parts by weight

Thus, coating was conducted by continuously spraying the above solutionof 50° C. onto the core which was previously heated at 50° C. Anincrease in the core was 30 mg. After spraying, the coated core wasdried, heated at 50° C. and a solution having the following compositionwas continuously sprayed to coat thereon.

Eudragit S 7.0 parts by weight Ethanol 70.0 parts by weight Water 18.8parts by weight Talc 3.5 parts by weight Polyethylene glycol 6000 0.7part by weight

An increase in weight was 30 mg.

Example 5

Manufacture of Calcitonin Capsules (Liquid)

Formulation 1

A liquid preparation containing calcitonin was manufactured according tothe following formulation and filled in HPMC capsules #3 to givecapsules each weighing 425 mg.

Calcitonin 10.0 parts by weight Glycerol 80.0 parts by weight Sucrosefatty acid ester [F-160 (trade name); 10.0 parts by weight manufacturedby Daiichi Kogyo Seiyaku K.K.]

Formulation 2

A liquid preparation containing calcitonin (CT) was manufacturedaccording to the following formulation and filled in the same capsulesas above to give capsules each weighing 425 mg.

Calcitonin 10.0 parts by weight PEG 400 80.0 parts by weight Sodiumdeoxycholate 10.0 parts by weight

After that, each of the capsules was coated with a solution having thefollowing composition.

Eudragit E 7.0 parts by weight Ethanol 70.0 parts by weight Water 19.5parts by weight Talc 3.5 parts by weight

Thus, coating was conducted by continuously spraying the above-mentionedsolution at 50° C. onto the core previously heated at 50° C. beingcoated with the inner layer already. An increase in weight by coatingwith the outer layer was 30 mg. After the spraying, the coated core wasdried and further coated with a solution of the following composition.

Eudragit S 7.0 parts by weight Ethanol 70.0 parts by weight Water 18.8parts by weight Talc 3.5 parts by weight Polyethylene glycol 6000 0.7part by weight

Thus, coating was conducted by continuously spraying the above-mentionedsolution of 50° C. onto the core which was previously heated at 50° C.coated with the inner layer. An increase in weight by coating with theouter layer was 30 mg.

Example 6

Manufacture of 5-Fluorouracil-Containing Capsules (Powder)

Powder containing 5-fluorouracil was manufactured according to thefollowing formulation and filled in HPMC capsules #3 to give capsuleseach weighing 150 mg.

5-Fluorouracil 50.0 parts by weight Cross povidone 50.0 parts by weight

The resulting capsules were coated with a solution having the followingcomposition.

Eudragit E 7.0 parts by weight Ethanol 70.0 parts by weight Water 19.5parts by weight Talc 3.5 parts by weight

The inner layer was coated by continuously spraying the above-mentionedsolution at 50° C. onto the core which was previously heated at 50° C.An increase in the core was 30 mg. After the spraying, the coated corewas dried and further coated with a solution of the followingcomposition.

Eudragit S 7.0 parts by weight Ethanol 70.0 parts by weight Water 18.8parts by weight Talc 3.5 parts by weight Polyethylene glycol 6000 0.7part by weight

The outermost layer was coated by continuously spraying theabove-mentioned solution of 50° C. onto the core which was previouslyheated at 50° C. coated with the inner layer. An increase in weight bycoating with the outer layer was 30 mg.

Example 7

Manufacture of 5-Fluorouracil Capsules (Liquid Preparation)

Formulation 1

A liquid preparation containing 5-fluorouracil was manufacturedaccording to the following formulation and filled in HPMC capsules #3 togive capsules each weighing 300 mg.

5-Fluorouracil 50.0 parts by weight Soybean oil 50.0 parts by weight

Formulation 2

A liquid preparation containing 5-fluorouracil was manufacturedaccording to the following formulation and filled in HPMC capsules #3 togive capsules each weighing 300 mg.

5-Fluorouracil 50.0 parts by weight PEG 400 50.0 parts by weight

Each of the capsules was subjected to a coating having the followingcomposition.

Eudragit E 7.0 parts by weight Ethanol 70.0 parts by weight Water 19.5parts by weight Talc 3.5 parts by weight

The inner layer was coated by continuously spraying the above-mentionedsolution at 50° C. onto the core which was previously heated at 50° C.An increase in the core was 30 mg. After the spraying, the coated corewas dried and further coated with a solution of the followingcomposition.

Eudragit S 7.0 parts by weight Ethanol 70.0 parts by weight Water 18.8parts by weight Talc 3.5 parts by weight Polyethylene glycol 6000 0.7part by weight

The outermost layer was coated by continuously spraying theabove-mentioned solution of 50° C. onto the core which was previouslyheated at 50° C. coated with the inner layer. An increase in weight bycoating with the outer layer was 30 mg.

Example 8

Manufacture of Capsules containing Sodium Betamethasone Phosphate(Powder)

Powder containing sodium betamethasone phosphate was manufacturedaccording to the following formulation and filled in HPMC capsules #2(weight: about 53 mg; and same being used hereinafter as well) to givecapsules each weighing 200 mg.

Sodium betamethasone phosphate 4.0 parts by weight Cross povidone 50.0parts by weight Lactose 46.0 parts by weight

Each of the capsules was subjected to a coating having the followingcomposition.

Eudragit E 7.0 parts by weight Ethanol 70.0 parts by weight Water 19.5parts by weight Talc 3.5 parts by weight

The inner layer was coated by continuously spraying the above-mentionedsolution at 50° C. onto the core which was previously heated at 50° C.An increase in the core was 40 mg. After the spraying, the coated corewas dried and further coated with a solution of the followingcomposition.

Eudragit S 7.0 parts by weight Ethanol 70.0 parts by weight Water 18.8parts by weight Talc 3.5 parts by weight Polyethylene glycol 6000 0.7part by weight

The outermost layer was coated by continuously spraying theabove-mentioned solution of 50° C. onto the core which was previouslyheated at 50° C. coated with the inner layer. An increase in weight bycoating with the outer layer was 40 mg.

Example 9

Manufacture of Sodium Betamethasone Phosphate (Liquid Preparation)

Formulation 1

A liquid preparation containing sodium betamethasone phosphate wasmanufactured according to the following formulation an filled in HPMCcapsules #2 to give capsules each weighing 400 mg.

Sodium betamethasone phosphate 5.0 parts by weight Soybean oil 95.0parts by weight

Formulation 2

A liquid preparation containing sodium betamethasone phosphate wasmanufactured according to the following formulation and filled in HPMCcapsules #2 to give capsules each weighing 400 mg.

Sodium betamethasone phosphate 5.0 parts by weight PEG 400 95.0 parts byweight

Each of the capsules was subjected to a coating having the followingcomposition.

Eudragit E 7.0 parts by weight Ethanol 70.0 parts by weight Water 19.5parts by weight Talc 3.5 parts by weight

The inner layer was coated by continuously spraying the above-mentionedsolution at 50° C. onto the core which was previously heated at 50° C.An increase in the core was 40 mg. After the spraying, the coated corewas dried and further coated with a solution of the followingcomposition.

Eudragit S 7.0 parts by weight Ethanol 70.0 parts by weight Water 18.8parts by weight Talc 3.5 parts by weight Polyethylene glycol 6000 0.7part by weight

The outermost layer was coated by continuously spraying theabove-mentioned solution of 50° C. onto the core which was previouslyheated at 50° C. coated with the inner layer. An increase in weight bycoating with the outer layer was 40 mg.

Example 10

Manufacture of Budesonide (Liquid Preparation)

Formulation 1

A liquid preparation containing budesonide was manufactured according tothe following formulation and filled in HPMC capsules #2 to givecapsules each weighing 400 mg.

Budesonide 5.0 parts by weight Soybean oil 95.0 parts by weight

Formulation 2

A liquid preparation containing budesonide was manufactured according tothe following formulation and filled in HPMC capsules #2 to givecapsules each weighing 400 mg.

Budesonide 5.0 parts by weight PEG 400 95.0 parts by weight

Each of the capsules was subjected to a coating having the followingcomposition.

Eudragit E  7.0 parts by weight Ethanol 70.0 parts by weight Water 19.5parts by weight Talc  3.5 parts by weight

The inner layer was coated by continuously spraying the above-mentionedsolution at 50° C. onto the core which was previously heated at 50° C.An increase in the core was 40 mg. After the spraying, the coated corewas dried and further coated with a solution of the followingcomposition.

Eudragit S  7.0 parts by weight Ethanol 70.0 parts by weight Water 18.8parts by weight Talc  3.5 parts by weight Polyethylene glycol 6000  0.7part by weight

The outermost layer was coated by continuously spraying theabove-mentioned solution of 50° C. onto the core which was previouslyheated at 50° C. coated with the inner layer. An increase in weight bycoating with the outer layer was 40 mg.

Example 11

Manufacture of Diclofenac Sodium (Liquid Preparation)

A liquid preparation containing diclofenac sodium was manufacturedaccording to the following formulation and filled in HPMC capsules #2 togive capsules each weighing 400 mg.

Diclofenac sodium 5.0 parts by weight Glycerol 95.0 parts by weight

Each of the capsules was subjected to a coating having the followingcomposition.

Eudragit E  7.0 parts by weight Ethanol 70.0 parts by weight Water 19.5parts by weight Talc  3.5 parts by weight

The inner layer was coated by continuously spraying the above-mentionedsolution at 50° C. onto the core which was previously heated at 50° C.An increase in the core was 40 mg. After the spraying, the coated corewas dried and further coated with a solution of the followingcomposition.

Eudragit S  7.0 parts by weight Ethanol 70.0 parts by weight Water 18.8parts by weight Talc  3.5 parts by weight Polyethylene glycol 6000  0.7part by weight

The outermost layer was coated by continuously spraying theabove-mentioned solution of 50° C. onto the core which was previouslyheated at 50° C. coated with the inner layer. An increase in weight bycoating with the outer layer was 40 mg.

INDUSTRIAL APPLICABILITY

offers a pharmaceutical preparation which does not undergo any change atall in stomach and in small intestine but firstly starts to disintegrateupon arriving at large intestine and, at the same time, quickly releasesthe drug therefrom. As a result thereof, it is now possible to offer apharmaceutical preparation which is useful for colon diseases such ascolon cancer, ulcerative colitis, constipation and diarrhea and forsystemic diseases such as osteoporosis.

What is claimed is:
 1. A capsule comprising a base layer consisting ofhydroxypropylmethylcellulose, a mixture of polyethylene glycol withhydroxypropylmethylcellulose, gelatin or agar, the outside surface ofsaid base layer being successively coated with an inner layer consistingof a cationic copolymer, and an outer layer consisting of an anioniccopolymer.
 2. The capsule according to claim 1, wherein the cationiccopolymer is a copolymer of methyl methacrylate with butyl methacrylateand dimethylaminoethyl methacrylate or polyvinylacetaldiethylaminoacetate.
 3. The capsule according to claim 1, wherein theanionic copolymer is at least one selected from a group consisting of acopolymer of methacrylic acid with methyl methacrylate,hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcelluloseacetate succinate, carboxymethylethylcellulose and cellulose acetatephthalate.
 4. The capsule according to any one of claims 1-3, whereinthe cationic copolymer and the anionic copolymer is each in an amount ofabout 5 mg to about 200 mg.
 5. The capsule according to claim 4, whereinthe cationic copolymer and the anionic copolymer is each in an amount ofabout 15 mg to about 60 mg.
 6. The capsule according to any one ofclaims 1-3, wherein the cationic copolymer and the anionic copolymer iseach, in terms of weight to the surface area of the capsule, in a rangeof about 0.08-0.13 mg/mm².
 7. A capsule preparation comprising thecapsule according to any one of claims 1-3, and a pharmacologicallyactive substance encapsulated in the capsule.
 8. The capsule preparationaccording to claim 7, wherein the pharmacologically active substance isat least one selected from a group consisting of polypeptides,anti-inflammatory agents, anti-tumor agents, antibiotics,chemotherapeutic agents, remedies for ulcerative colitis, remedies forirritable colon syndrome, steroidal preparations, vitamins, drugs forconstipation, anti-sense drugs and immunosuppressants.
 9. The capsulepreparation according to claim 7, wherein the pharmacologically activesubstance is contained in a liquid preparation, said liquid preparationbeing encapsulated in the capsule.
 10. The capsule preparation accordingto claim 9, wherein the liquid preparation is at least one selected fromthe group consisting of glycerol, soybean oil, polyethylene glycol 400(PEG 400), docosahexaenoic acid, eicosapentaenoic acid, pirotiodecane,sesame oil, safflower oil, cotton seed oil and olive oil.
 11. Thecapsule preparation according to claim 9, further comprising anabsorbefacient compounded with the liquid preparation.
 12. The capsulepreparation according to claim 11, wherein the absorbefacient isselected from a group consisting of sucrose fatty acid ester,glycyrrhizinate, glycyrrhetinic acid, bile acid and conjugated compoundthereof, pirotiodecane, glycerol fatty acid ester, adipic acid, basicamino acid, polyethylene glycol, sodium caprate, sodium dodecyl sulfateand sodium deoxycholate.
 13. The capsule preparation according to claim7, which disintegrates in the lower gastrointestinal tracts and is fororal administration.
 14. The capsule according to any one of claims 1-3,which disintegrates in the lower gastrointestinal tracts and is for oraladministration.
 15. A method of making a capsule comprising coating onthe outside surface of a base layer of the capsule an inner layerconsisting of a cationic copolymer, and further coating on said innerlayer an outer layer consisting of an anionic copolymer.
 16. The methodaccording to claim 15, wherein the cationic copolymer is a copolymer ofmethyl methacrylate with butyl methacrylate and dimethylaminoethylmethacrylate or polyvinylacetal diethylaminoacetate.
 17. The methodaccording to claim 15, wherein the anionic copolymer is at least oneselected from a group consisting of a copolymer of methacrylic acid withmethyl methacrylate, hydroxypropylmethylcellulose phthalate,hydroxypropylmethylcellulose acetate succinate,carboxymethylethylcellulose and cellulose acetate phthalate.
 18. Themethod according to any one of claims 15-17, wherein the cationiccopolymer and the anionic copolymer is each coated in an amount of about5 mg to about 200 mg.
 19. A method of making a capsule preparationcomprising encapsulating a pharmacologically active substance in acapsule obtained by the method according to any one of claims 15-17. 20.The method according to claim 19, wherein the pharmacologically activesubstance is at least one selected from a group consisting ofpolypeptides, anti-inflammatory agents, anti-tumor agents, antibiotics,chemotherapeutic agents, remedies for ulcerative colitis, remedies forirritable colon syndrome, steroidal preparations, vitamins, drugs forconstipation, anti-sense drugs and immunosuppressants.
 21. The methodaccording to claim 20, wherein the pharmacologically active substance isdissolved or dispersed in a liquid preparation, and the liquidpreparation is encapsulated in the capsule.
 22. The method according toclaim 21, wherein the liquid preparation is at least one selected fromthe group consisting of glycerol, soybean oil, polyethylene glycol 400(PEG 400), docosahexaenoic acid, eicosapentaenoic acid, pirotiodecane,sesame oil, safflower oil, cotton seed oil and olive oil.
 23. The methodaccording to claim 21, further comprising an absorbefacient compoundedwith the liquid preparation.
 24. The method according to claim 23,wherein the absorbefacient is selected from the group consisting ofsucrose fatty acid ester, glycyrrhizinate, glycyrrhetinic acid, bileacid and conjugated compound thereof, pirotiodecane, glycerol fatty acidester, adipic acid, basic amino acid, polyethylene glycol, sodiumcaprate, sodium dodecyl sulfate and sodium deoxycholate.